The steadily high mortality associated with melanoma is in part due to the limitations of predicting the melanoma recurrence, especially for patients with early-stage disease. While currently available clinicopathological characteristics provide some information, their ability to predict outcome in a more personalized fashion is limited. Recent studies have proposed a number of molecular predictors in pathways related to melanoma progression, but these are too general to cater the prognostic assessment to individual patients and will still require independent validation. The central hypothesis of our study is that the melanoma recurrence is modulated but common or rare germline genetic factors. We postulate that such loci will be associated with the risk of early recurrence in clinically favorable melanomas, and potentially with protective effect in less favorable advanced stages manifesting with late to no relapse. In support of the proposed hypothesis we have generated highly promising preliminary data demonstrating that the germline genetic factors may impact melanoma clinical outcomes. Building on these observations we propose a comprehensive genetic profiling of germline and tumor specimens of melanoma patients ascertained at NYUMC to identify novel germline genetic loci associated with the risk of melanoma recurrence. In Specific Aim 1 we will perform germline whole-genome sequencing (WGS) and tumor whole-transcriptome sequencing (RNA-seq) on Ashkenazi Jewish (AJ) early stage melanoma patients (stage I/II) on extremes of melanoma recurrence: comparing patients with early recurrence (n=100) versus late or no recurrence (n=100). The germline and tumor data will be integrated in our newly developed strategy to identify biologically most plausible candidates associated with risk of recurrence. The selection of AJ ancestry will significantly improve the design by reducing the genetic heterogeneity and enhancing the analytical power by identification of founder alleles associated with recurrence, that are shared among AJ patients. In Specific Aim 2 we will test the identified genetic loci in Aim 1 for their association with recurrence outcomes and other clinical indicators in a melanoma cohort of 1,354 patients of predominantly non-AJ European ancestries. In Specific Aim 3, the novel germline loci associated with melanoma recurrence will be functionally tested in zebrafish melanoma model, identifying targetable variants with biological role in melanoma progression and outcome. The novel germline variants/mutations will be, in parallel, incorporated into prognostic melanoma model using an additional population of 1,268 melanoma patients from NYULMC subsets. The findings generated in this study will not only reveal novel markers of melanoma prognosis with more personalized clinical potential, but the comprehensive exploration of their biological role, as proposed, may point to novel molecular pathways in melanoma progression. Hence, besides improved clinical follow-up care of patients at early stage of melanoma, the study's impact is in the discovery of putatively novel targets of more personalized adjuvant therapies tailored for the melanoma patients with early disease but high risk of recurrence.